惡性腫瘤長期佔據全球死因第一位，其中胰臟癌由於初期不易診斷與治療困難導致高死亡率，傳統治療胰臟癌的方法包含了手術切除、化學藥物治療以及放射線治療，因手術切除復發機率高，通常會配合化學藥物進行複合治療。化學藥物治療雖能抑制癌細胞，但癌細胞能透過代謝重整減弱療效並增強化學藥物抗性。代謝重整是癌症典型特徵，細胞會大量利用葡萄糖、脂質、胺基酸等快速產生能量支持其增殖，而在缺乏血管新生的腫瘤內部，呈現一個低氧、低營養素的環境，此時腫瘤內部細胞可能會改變其代謝模式來適應此環境，使得傳統治療的效果不如以往，先前研究已指出具有化學藥物抗性的胰臟癌細胞會生成更多的初級纖毛，並且在存活期較短的胰臟癌病患的組織切片染色中也有發現初級纖毛的存在，而癌細胞高度仰賴麩醯胺酸促進生長。本實驗中將胰臟癌細胞培養在缺乏麩醯胺酸的環境中三個月後進行後續實驗 (以下簡稱-QQ細胞)，實驗結果發現在缺乏麩醯胺酸環境中，-QQ細胞會增加麩醯胺酸代謝 (GS、GLS1)、初級纖毛生成 (IFT88、IFT43、KIF7) 相關基因以及脂肪酸轉位酶 (CD36) 的表達量，並減少脂質生合成基因 (ACC1、FAS、SREBP1) 的表達量，同時發現脂肪酸攝取變多，Cisplatin (CPT) IC50上升，但麩醯胺酸缺乏、初級纖毛生成與抗藥性之間的關聯性仍有待探討。在-QQ細胞中敲低IFT88後CD36表達下降，也減少了脂肪酸攝取與CPT IC50，此結果顯示，-QQ細胞增強了對於CPT的抗性有可能是透過IFT88促進CD36表達增強脂肪酸攝取，進一步影響CD36表達與脂肪酸攝取；而敲低-QQ細胞中的CD36實驗結果顯示，細胞降低了脂肪酸攝取與CPT抗性；在-QQ細胞中分別敲低GS與GLS1，發現IFT88與CD36表達量皆有上升，也增加了脂肪酸攝取與CPT抗性。給予-QQ細胞不同種類的高濃度脂肪酸會抑制細胞生長，而給予細胞不同種類的低濃度脂肪酸與CPT共同處理，發現OA、LA、ALA、EPA以及DHA降低細胞對於CPT的敏感性。綜合上述結果顯示，-QQ細胞中IFT88透過調控CD36影響細胞脂肪酸攝取，進而增加細胞對於CPT的抗性，而GS與GLS1共同在其中扮演負調控的角色，抑制IFT88與CD36的表達量，而給予低濃度OA、LA、ALA、EPA以及DHA增加了細胞對於CPT的抗性。

Malignant tumors have consistently ranked as the leading cause of death worldwide. Among these, pancreatic cancer exhibits high mortality rates due to difficulties in early diagnosis and treatment. Conventional treatments for pancreatic cancer include surgical resection, chemotherapy, and radiation therapy. However, because of the high recurrence rate after surgery, combination therapy with chemotherapy is often employed. While chemotherapy can inhibit cancer cells, these cells often adapt through metabolic reprogramming, reducing drug efficacy and enhancing resistance. Metabolic reprogramming is a hallmark of cancer, as cancer cells extensively utilize glucose, lipids, and amino acids to rapidly generate energy to sustain their proliferation. Within tumors lacking angiogenesis, the internal environment is often hypoxic and nutrient-deprived. Under these conditions, tumor cells may alter their metabolic pathways to adapt, thereby reducing the effectiveness of traditional treatments. Previous studies have indicated that chemoresistant pancreatic cancer cells produce more primary cilia and that primary cilia are also observed in tissue samples from patients with shorter survival times. Additionally, cancer cells heavily rely on glutamine to promote growth. In this study, pancreatic cancer cells were cultured in a glutamine-deprived environment for three months (hereafter referred to as -QQ cells) for subsequent experiments. Results showed that under glutamine-deprived conditions, -QQ cells exhibited increased expression of genes associated with glutamine metabolism (GS, GLS1), primary cilia formation (IFT88, IFT43, KIF7), and fatty acid translocase (CD36), while genes related to lipid biosynthesis (ACC1, FAS, SREBP1) were downregulated. Furthermore, increased fatty acid uptake and a higher Cisplatin (CPT) IC50 were observed. However, the relationship between glutamine deprivation, primary cilia formation, and drug resistance remains to be clarified. Knockdown of IFT88 in -QQ cells resulted in decreased CD36 expression, reduced fatty acid uptake, and a lower CPT IC50. This finding suggests that the enhanced CPT resistance in -QQ cells may be mediated by IFT88 promoting CD36 expression to increase fatty acid uptake, which further influences CPT resistance. Additionally, knockdown of CD36 in -QQ cells showed a reduction in both fatty acid uptake and CPT resistance. When GS and GLS1 were separately knocked down in -QQ cells, both IFT88 and CD36 expression levels were elevated, along with increased fatty acid uptake and enhanced CPT resistance. Treating -QQ cells with different types of high-concentration fatty acids inhibited cell growth. When -QQ cells were co-treated with various low-concentration fatty acids and CPT, it was observed that OA, LA, ALA, EPA, and DHA reduced the cells' sensitivity to CPT. These results collectively indicate that IFT88 in -QQ cells influence fatty acid uptake through the regulation of CD36, thereby contributing to increased CPT resistance. GS and GLS1 act as negative regulators in this process by suppressing the expression of IFT88 and CD36. Treatment with low concentrations of OA, LA, ALA, EPA, and DHA increased the cells' resistance to CPT.

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